Stress is a major causal factor in the etiology of a number of psychiatric-related disorders. Individuals exposed to life-jolting, traumatic events, such as natural disasters, war or personal injury, may develop post- traumatic stress disorder (PTSD), a condition which results in the individual's inability to function in everyday life. However, through it all, there are those individuals that remain stress resilient and persevere in the face of intense stress. Currently, there is very little known about the mechanisms underlying the production of stress resilience. The long-term goal of this research is to elucidate the pathways and mechanisms in the brain involved in the generation of stress resilience which will be useful for preventive and therapeutic treatment of anxiety-related disorders. The basolateral nucleus of the amygdala (BLA) is a brain region that is essential for the integration and processing of sensory and memory information into stress responses and emotion. BLA activity is reflective of the balance of inhibitory and excitatory tone which is modulated, in part, by neuropeptide Y (NPY) and corticotrophin-releasing factor (CRF). In the BLA, NPY not only buffers the actions of CRF, but produces long term stress resilience. The overarching hypothesis is that NPY decreases the output of the BLA by reducing the excitability of glutamatergic output neurons via acute and chronic downregulation of HCN (hyperpolarization-activated, cyclic nucleotide-gated) channel function which carries Ih. Preliminary studies demonstrate that NPY and CRF receptors present on glutamatergic cells in the BLA, exert opposing physiological actions on an important ion channel, (Ih), which governs the excitability of the BLA. That both of these peptides affect Ih makes this molecule a nexus for two different stress signals in modulating the activity of principal neurons of the BLA. Our central hypotheses are that: 1) acutely, NPY produces anxiolysis by decreasing BLA output through inhibition of the tonically-active H-current (Ih) in BLA pyramidal neurons, and that 2) repeated treatment with NPY results in a prolonged reduction in expression of the postsynaptic HCN channels which carry Ih; and that 3) stressful stimuli, via CRF, increases HCN activity and ultimately expression in BLA output cells. The identification of the HCN channels as potential targets of neuronal plasticity in this model of induced resilience is exciting and such information is crucial for the development of pharmacopoeia that could aid those individuals exposed to stressful environments. PUBLIC HEALTH RELEVANCE: This application centers on the multidisciplinary elucidation of a brain circuit involved in buffering the deleterious effects of stress on an individual. This project will identify mechanisms underlying stress resilience and provide information that is crucial for the development of novel therapeutics for the treatment, or prevention, of stress- and trauma-related disorders. This research is congruent with the strategic plan of the NIMH to promote an integrative understanding of basic brain-behavior processes, including the identification of novel factors associated with stress resilience and vulnerability.